PT  - JOURNAL ARTICLE
AU  - Tarcha, Eric J.
AU  - Chi, Victor
AU  - Muñoz-Elías, Ernesto J.
AU  - Bailey, David
AU  - Londono, Luz M.
AU  - Upadhyay, Sanjeev K.
AU  - Norton, Kayla
AU  - Banks, Amy
AU  - Tjong, Indra
AU  - Nguyen, Hai
AU  - Hu, Xueyou
AU  - Ruppert, Greg W.
AU  - Boley, Scott E.
AU  - Slauter, Richard
AU  - Sams, James
AU  - Knapp, Brian
AU  - Kentala, Dustin
AU  - Hansen, Zachary
AU  - Pennington, Michael W.
AU  - Beeton, Christine
AU  - Chandy, K. George
AU  - Iadonato, Shawn P.
TI  - Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease
AID  - 10.1124/jpet.112.191890
DP  - 2012 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 642--653
VI  - 342
IP  - 3
4099  - http://jpet.aspetjournals.org/content/342/3/642.short
4100  - http://jpet.aspetjournals.org/content/342/3/642.full
SO  - J Pharmacol Exp Ther2012 Sep 01; 342
AB  - The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.